N-(5-indanylsulfonyl)-N'-(4-chlorophenyl)urea, a novel agent equally cytotoxic to nonproliferating human colon adenocarcinoma cells.
Diarylsulfonylureas have been shown to have therapeutic activity against rodent and human tumor models, notably causing regressions in some lines of human colon adenocarcinomas in mice. At present the mechanism of cytotoxicity is unknown, although preliminary data implicate mitochondria as a potential site of action. In this study, the cytotoxicity of the diarylsulfonylurea N-(5-indanylsulfonyl)-N'-(4-chlorophenyl)urea (ISCU) has been examined in GC3/c1 human colon adenocarcinoma cells. At cytotoxic concentrations of ISCU, in the presence of albumin as a drug binding species, there was only slight inhibition of [3H]thymidine and [3H]uridine incorporation at concentrations of ISCU up to 140 micrograms/ml and no inhibition of synthesis of protein as determined by incorporation of L-leucine. In the absence of albumin, incorporation of [3H]thymidine into DNA or [3H]uridine into RNA was inhibited at greater than 70 micrograms/ml and 140 micrograms/ml, respectively. As ISCU is highly bound to serum albumin (greater than 99%), it would appear that inhibition of nucleic acid synthesis occurs only at supralethal concentrations of ISCU. The cytotoxicity of ISCU in proliferating or quiescent cell populations was examined. GC3/c1 cells grown in medium containing 0.5% fetal calf serum (FCS) had a 60% reduction in rate of growth, but were more sensitive than cells exposed for 24 h in 10% FCS-medium (IC50 1.9 and 31 micrograms/ml, respectively). When the albumin concentration was adjusted (240 mg/100 ml) to allow equivalent drug binding, IC50 values were similar. In cultures of GC3/c1 cells growth rate was related to the concentration of FCS. In the absence of serum, growth rate was 2.5 to 3.2% that of exponentially growing control cultures in the presence of 10% FCS. Addition of FCS to quiescent cultures after 1 to 6 days in serum-free conditions resulted in immediate growth of cells. Clonogenic potential was also unchanged for at least 6 days under serum-free conditions. Under these conditions, where albumin concentration was adjusted to be equivalent to medium containing 10% FCS, sensitivity of proliferatively quiescent GC3/c1 cells was similar to that in exponentially growing control cultures in which the population doubling time was approximately 22 h. Further, there was no recovery of clonogenic potential when cells were exposed for 24 h to ISCU and maintained in a quiescent state for up to 4 days prior to serum stimulation. These data suggest that the cytotoxic effects of ISCU are independent of the proliferative state of the cell population.(ABSTRACT TRUNCATED AT 400 WORDS)
Houghton
P J
PJ
Dept. of Biochemical and Clinical Pharmacology, St Jude Children's Research Hospital, Memphis, Tennessee 38101.
Bailey
F C
FC
Germain
G S
GS
Grindey
G B
GB
Witt
B C
BC
Houghton
J A
JA
D000230:Adenocarcinoma / Q000473:pathology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001790:Blood Physiological Phenomena; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000473:pathology*; D003470:Culture Media; D006801:Humans; D012709:Serum Albumin / Q000378:metabolism; D013453:Sulfonylurea Compounds / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D003470:Culture Media; D012709:Serum Albumin; D013453:Sulfonylurea Compounds; C058179:sulofenur